Nk-2 antagonist basic linear compounds and formulations containing them

ABSTRACT

The present invention describes compounds with formula (I) having linear structure basic properties useful as NK-2 antagonists; pharmaceutical compositions containing said compounds are also described and processes for their preparation.

FIELD OF THE INVENTION

The present invention relates to antagonists of tachykinins, inparticular of neurokinin A, and to their use in pharmaceuticalformulations.

In particular, the present invention relates to compounds with thefollowing general formula:

where:

X1 is a —NR6-CO—, —CO—, —NR6-CS— group

R1 is an aryl group selected from pyridine, thiophene, benzene,naphthalene, diphenyl, phenylthiophene, benzothiophene, benzofuran,N-indole by an R7 group, where said aryl group may also be substitutedby one or more independent groups selected from halogen, C1-C6 alkyloptionally substituted by not more than three fluorine atoms (i.e.trifluoromethyl group), C1-C6 alkyloxyl, optionally substituted by notmore than three fluorine atoms (i.e. trifluoromethyloxyl group), —OH,—NHR7, —N(R7)2, —SR7, —CONHR7, —COR7, —COOR7, —R8COOR7, —OR8COOR7,—R8COR7, —CONHR7, —R8CONHR7, —NHCOR7, -nitro, where R7 is hydrogen orC1-C6 alkyl with a linear or branched chain, and R8 is a C1-C6 alkylenegroup with a linear or branched chain;

R6 is selected from a group consisting of hydrogen or a C1-C6 alkyl witha linear or branched chain;

the broken line indicates a possible double bond and n and m mayindependently be 0, 1, 2;

R9 and R10 are selected independently in the hydrogen, C1-C6 alkyl groupor may be connected to form an aromatic group selected in a phenylgroup;

X2 is selected in the group formed of —(CH2)p-, —(CH2)q-CO—,—(CH2)s-O—(CH2)q-, —CH═CH—, —CH═CH—CO—, CH═CH—O—(CH2)q- where p may be2, 3, 4; q may be 2, 3, 4: and s may be 1, 2;

R2 is selected from a group consisting of an aryl-alkyl or aryl radicalwhere the aryl part is selected in a group consisting of benzothiophene,indole, pyridine, pyrrol, benzofuran, thiophene, benzene, naphthalene,imadazole, diphenyl, and may optionally be substituted by one or moresubstituents selected independently from halogen, C1-C6 alkyl optionallysubstituted by not more than three fluorine atoms (i.e. trifluoromethylgroup), C1-C6 alkyloxyl, optionally substituted by not more than threefluorine atoms (i.e. trifluoromethyloxyl group), —OH, —NHR7, —N(R7)2,—SR7, —CONHR7, —COR7, —COOR7, —R8COOR7, —OR8COOR7, —R8COR7, —CONHR7,—R8CONHR7, —NHCOR7, -nitro, where R7 is hydrogen or C1-C6 alkyl with alinear or branched chain, and R8 is a C1-C6 alkylene group with a linearor branched chain;

R3 contains at least a basic amino group and is selected from a groupwith general formula:—R₄—X₃—R₅

where R4 is selected from a group consisting of:

-   -   an —NR6- amino group;    -   an aliphatic heterocycle containing one or two heteroatoms        selected from N, S and O, and optionally substituted by one or        two C1-C6 alkyl groups;

X3 can be a simple bond or is selected in the group consisting of(CH2)t-, —CO—, —O—(CH2)t-, —O—, —NH—CO—CH2-, —NH—CO— where t can be 1,2, 3;

R5 is:

-   -   an aliphatic heterocycle, selected in the group consisting of        pyrrolidine, piperidine, morpholine, tetrahydropyran,        1,4-dioxa-8-azaspiro[4,5]decane, dioxane, optionally substituted        by one or more C1-C6 alkyl, hydroxymethyl, —OH, cyanomethyl and        C1-C6 alkyloxy groups;

a group selected from —NR₁₁R₁₂, —OR11 where R_(11,) R₁₂ areindependently selected in the group: hydrogen, C1-C6 alkyl;

-   -   an aryl selected from thiophene, pyridine, furane or phenyl        optionally substituted by one or more halogen, C1-C6 alkyl,        C1-C6 alkyloxy and OH groups;

The present invention also includes “retro-inverted” compounds, that is,compounds having the structure of general formula (I), but wherein oneor more amide bonds are reversed.

The presence of at least one amino group in R3, which imparts a basiccharacteristic to the compounds, may be considered an importantstructural characteristic.

The present invention also includes the pharmaceutically acceptablesalts of compounds of formula (I) with organic and inorganic acidsselected in the group: hydrochloric, sulphuric, phosphoric, acetic,trifluoroacetic, oxalic, malonic, maleic, fumaric, succinic, tartaricand citric acids. Moreover, all possible diastereoisomers or mixturesthereof, caused by introducing residues or groups having chiral centresinto the sequence of general formula (I), are an integral part of thepresent invention.

The compounds of formula (I), with receptor antagonist activity of thetachykinins, prove useful to treat diseases wherein the neurokinin Aplays a pathogenetic role.

STATE OF THE ART

Tachykinins are a family of at least three peptides, known as SubstanceP, Neurokinin A (NKA) and Neurokinin B (NKB).

Research in the field of tachykinin antagonists, principally based onsingle or multiple substitution of the amino acids of the sequence ofpeptide agonists of Substance P and of the other tachykinins, has led tothe discovery of nonapeptides containing one or more units ofD-tryptophan (Regoli et al. Pharmacol 28,301 (1984)). However, theproblems deriving from the pharmacological use of high molecular weightpeptides (multiple sites of enzymatic hydrolytic attack, poorbio-availability, rapid hepatic and renal excretion) induced research ofthe minimum peptide fragment still capable of exerting antagonistactivity. These studies led to the detection of adequately derivatizedbicyclic and monocyclic peptides, antagonists of neurokinin A (PatentApplications WO9834949 and WO200129066).

Various compounds have been claimed as selective antagonists ofSubstance P, for example in WO9519966 and WO99845262, but, besides beingselective for the NK1 receptor, these compounds have differentstructural characteristics to those of the present invention, theprincipal of which is the lack of a basic amino group.

Among NK1 antagonists, we can also mention those described inWO200014109; in these, there is no alpha, alpha-disubstituted aminoacid, and the basic group, although present, is in very differentpositions with respect to the position of the compounds forming theobject of the present invention.

Also in EP394989 the compounds with NK1 activity described do notgenerally have a basic group and do not have an alpha,alpha-disubstituted-amino acid. In Biorganic & Med. Chem. (1994), 2 (2),101-113 (S. Boile et al.) compounds are described with NK2 antagonistactivity containing an alpha, alpha-disubstituted phenylalanine, butthey do not have basic characteristics and cannot be associated with thestructure described with general formula I.

WO9404494 describes NK1 antagonists that have a alpha,alpha-disubstituted amino acid, but whose structure does not correspondto general formula (I), in particular for the presence, among others, ofan —O—CO-group in place of X1.

DETAILED DESCRIPTION OF THE INVENTION

It has been surprisingly found, and this is a characteristic of thepresent invention, that the compounds of general formula (I) as abovedefined, of a non-peptide nature, have improved characteristics ininhibiting bonding of tachykinins on the NK2 receptor and in vivoantagonist activity with respect to the products disclosed in the priorart patents cited above.

A preferred group of compounds of the present invention comprises thecompounds that can be described by general formula (I) where the aminoacid residue of general formula II:

is selected in the group consisting of amino acid residues of:1-aminocyclohexane-1-carboxylic acid (Ac6c),1-aminocyclopentane-1-carboxylic acid (Ac5c),1-aminocyclopent-3-ene-1-carboxylic acid (Ac5c),1-aminoindane-1-carboxylic acid(1-Aic), 2-aminoindane-2-carboxylic acid(2-Aic), 2-aminotetraline-2-carboxylic acid (2-Atc), and the othergroups are as defined above.

A group of preferred compounds according to the present inventionconsist of compounds having general formula (I), wherein:

-   -   X1 is a CO group

R1 is an aryl group selected from naphthalene, benzothiophene,benzofuran, N-indole substituted by an R7 group; where said aryl groupis optionally substituted by one or more groups independently selectedfrom halogen, C1-C6 alkyl optionally substituted by not more than threefluorine atoms (i.e. trifluoromethyl group), C1-C6 alkyloxy optionallysubstituted by not more than three fluorine atoms (i.e.trifluoromethoxyl group), —OH, —NHR7, —N(R7)2, —SR7, —CONHR7, —COR7,—COOR7, —R8COOR7, —OR8COOR7, —R8COR7, —CONHR7, —R8CONHR7, —NHCOR7,-nitro, where R7 is hydrogen or a linear or branched C1-C6 alkyl chain,and R8 is a linear or branched C1-C6 alkylene group;

-   -   R6 is selected from a group consisting of hydrogen or a linear        or branched C1-C6 alkyl chain;    -   the amino acid residue of general formula II:

is selected in the group consisting of amino acid residues of:1-aminocyclohexane-1-carboxylic acid (Ac6c),1-aminocyclopentane-1-carboxylic acid (Ac5c),

R2 is a phenylmethyl group optionally substituted on the phenyl portionby one or two groups independently selected from halogen, C1-C6 alkyl,C1-C6 alkyloxy, and OH

-   -   X2 is as defined hereinbefore    -   R3 contains at least one basic amino group and represents a        group:        —R₄—X₃—R₅

wherein R4 is selected in the group:

-   -   an —NR6- amino group,    -   an aliphatic heterocycle selected from piperidine, piperazine,        pyrrolidine optionally substituted by one or two C1-C6 alkyl        groups;

X3 may be a simple bond or is selected in the group consisting of—(CH2)t-, —CO—, where t may be 1, 2, 3;

R5 is:

-   -   an aliphatic heterocycle selected in the group consisting of        tetrahydropyran, morpholine, piperidine, optionally substituted        by one or more groups C1-C6 alkyl, hydroxymethyl, —OH,        cyanomethyl, and C1-C6 alkyloxy;    -   a group selected from —NR₁₁R₁₂, —OR11 where R_(11,) R₁₂ are        independently selected in the group: hydrogen, C1-C6 alkyl;    -   an aryl selected from thiophene, furane or phenyl optionally        substituted by one or more halogen, C1-C6 alkyl, C1-C6 alkyloxy        or OH groups;

Particularly preferred amongst these are the compounds wherein:

XI is a —CO-group;

RI is a benzothiophene group, which may optionally be substituted by oneor two groups selected independently from halogen, C1-C6 alkyloptionally substituted by not more than three fluorine atoms,

the amino acid residue of general formula (III) is1-aminocyclopentane-1-carboxylic acid(Ac5c),

R6 is hydrogen;

R2 is phenyl-methyl, with the phenyl group optionally substituted by aC1-C6 alkyl;

X2 is selected in the group consisting of —(CH2)p-, —(CH2)q-CO—,—(CH2)s-O—(CH2)q-, —CH═CH—, —CH═CH—CO—, where p is 3; q is 2: and s is1;

R3 contains at least one basic amino group and represents a group—R₄—X₃—R₅

wherein

R4 is selected from a group consisting of:

-   -   an —NR6- amino group;    -   an aliphatic heterocycle selected from piperidine and piperazine

X3 may be a simple bond or is selected from the group consisting of—(CH2)t-, —CO—, where t may be 1, 2, 3;

R5 is:

-   -   a tetrahydropyran,    -   a group selected from —NR₁₁R₁₂, —OR11 where R_(11,) R₁₂ are        independently selected in    -   a phenyl.

R6 is hydrogen;

Among the terms used in the present description the following arepreferred: for halogens a group selected from fluorine, chlorine,bromine or iodine; for C1-C6 alkyl a group selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, ter-butyl or, when optionally substitutedby fluorine, trifluoromethyl; for C1-C6 alkyloxy a group wherein thealkyl part is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,ter-butyl or, when optionally substituted by fluorine, trifluoromethyl;for C1-C6 alkylene a group selected from methylene, ethylene,trimethylene, and tetramethylene.

The compounds of the present invention have shown an antagonist activitytowards the action of Substance P, Neurokinin A, and Neurokinin B,although they proved particularly selective in antagonizing the actionof Neurokinin A.

They may therefore be used as pharmaceuticals for the treatment andprevention of diseases in which tachykinins in general, and inparticular Neurokinin A, are involved as neuromodulators.

Purely as an example, we can list respiratory diseases such as asthma,allergic rhinitis, and chronic obstructive bronchitis, ophthalmicdiseases such as conjunctivitis, skin diseases such as allergic andcontact dermatitis, and psoriasis, intestinal disorders such asirritable colon syndrome, ulcerous colitis and Crohn's disease, gastricdiseases, urinary diseases such as cystitis and incontinence, erectiledysfunctions, diseases of the nervous central system such as anxiety,depression or schizophrenia, tumor diseases, autoimmune diseases ordiseases related to AIDS, cardiovascular diseases, neuritis, neuralgiaand treatment of pain, in particular visceral pain, inflammatoryprocesses, such as osteoarthritis or rheumatoid arthritis.

The compounds of general formula (I), as defined above, can be preparedaccording to methods described in the literature and well known to thoseskilled in the art, such as amide condensation, substitution, additionor reductive amination reactions.

For example, these compounds can be synthesized by condensing the partof the molecule with basic characteristics, having the structure offormula III

with the other part of the molecule, as an acid having general formulaIV or as an oxazolidinone of formula V

according to well known methods. In the part more specifically dedicatedto the examples, various diagrams provide detailed descriptions of thesynthetic paths followed for the various compounds described, althoughthese synthetic paths and relative diagrams are provided purely asexamples and must not be considered to be limiting.

The compounds of the present invention may exist in various isomericforms. In fact, whereas the configuration of the carbon bonded to thesubstituent R₅ is univocally prefixed by using during synthesis thespecific isomer of the amino acid derivative, frequently the otherinitial products can consist of mixtures of stereoisomers that aredifficult separation. Therefore, the compounds of the present inventioncan be obtained as mixtures of diastereoisomers. These mixtures can beresolved by chromatography. The compounds of formula (1) can however beused both as single enantiomers and in the form of mixtures of isomers.Some representative examples of the present invention and of the methodfor the synthesis thereof are provided below.

Synthesis Diagram for Compounds 6 and 7

EXAMPLE 1 1R-(1-Hydroxymethyl-2-phenyl-ethyl)-carbamic acid tert-butylester (1)

To a solution of D-phenyl alaninol (1.5 g, 9.9 mmol, 1 eq) in anhydrousTHF (10 mL) under magnetic stirring is added di-t-butyl dicarbonate (2.7mL, 11.9 mmol, 1.2 eq.) and then distilled under reduced pressure. Theisolated residue is recrystallized from AcOEt/hexane to give 2.1 g (8.35mmol, yield=84%) of (1-Hydroxymethyl-2-phenyl-ethyl)-carbamic acidtert-butyl ester (1). HPLC (method A): Rt=8.89 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.31 (s, 9H, C(CH₃)₃); 2.54 (m, 1H,PhCHH); 2.81 (dd, 1H, PhCHH, J=5.4, 13.5 Hz); 3.15-3.40 (m, 2H, CH ₂OH);3.44-3.70 (m, 1H, OH); 4.63-4.77 (m, 1H, NHCH); 6.59 (d, 1H, NH, J=8.4Hz), 7.07-7.14 (m, 5H, Ph).

EXAMPLE 2 1R-(1-Formyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester(2)

To a solution of oxalyl chloride distilled (1.5 mL, 11.94 mmol, 1.5 eq.)in DCM (20 mL) under magnetic stirring kept at −60° C. (a dryice/acetone bath) under a nitrogen atmosphere is added anhydrous DMSO(1.70 mL, 23.87 mmol, 3.0 eq.) and the resulting mixture stirred at −60°C. for 10 minutes. A solution of(1-Hydroxymethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (1) (2.0g, 7.96 mmol, 1.0 eq.) in DCM (40 mL) at −60° C. is then added and theresulting mixture is kept under stirring for 15 minutes. Finally, DIPEA(8.15 mL, 47.75 mmol, 6.0 eq.) is added and the solution obtained keptat −60° C. for a further 5 minutes.

To the reaction left to heat to room temperature 60 mL of water areadded and the resulting biphasic mixture is left under stirring for 10minutes. The mixture is transferred to a separatory funnel, DCM (60 mL)is added, the mixture is shaken and the phases separated. The organicphase is then washed with a 1N solution of HCl (100 mL) and brine (100mL), anhydrified on anhydrous Na₂SO₄, filtered and brought to dryness.(1-Formyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (2) is obtainedas a pale yellow solid (1.98 g, 7.96 mmol, quantitative yield), cleanedby H¹-NMR which is used without further purification.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.34 (s, 9H, C(CH₃)₃); 2.71 (dd, 1H,PhCHH, J=10.2, 13.8 Hz); 3.09 (dd, 1H, PhCHH, J=10.2, 13.8 Hz);3.98-4.18 (m, 1H, NHCH); 7.12-7.44 ((m, 5H, Ph); 9.52 (s, 1H, COH).

EXAMPLE 3 4R-4-tert-butoxycarbonylamino-5-phenyl-pent-2-enoic acid ethylester (3)

A mixture of (1-formyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester(2) (1.98 g, 7.96 mmol, 1 eq.) and(carbethoxymethylene)triphenylphosphorane (2.93 g, 8.42 mmol, 1.06 eq.)in DCM (70 mL) is kept under magnetic stirring at room temperature for 3hour. The solution is concentrated under reduced pressure and the rawproduct obtained is purified by flash chromatography eluting with amixture of petroleum ether/ethyl acetate 90:100 until the firstby-product (R_(f)=0.65 in petroleum ether: AcOet 90:10) is obtained andthen with a mixture of petroleum ether: AcOEt 80:20. The fractionscontaining the desired product are recombined and the solvent distilledunder reduced pressure. 4tert-butoxycarbonylamino-5-phenyl-pent-2-enoicacid ethyl ester (3) is obtained as a crystalline white solid (2.15 g,6.73 mmol, yield=84.6%).

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.20 (t, 3H, CH₂ CH ₃, J=7.0 Hz); 1.31 (s,9H, C(CH₃)₃); 2.71 (dd, 1H, PhCHH, J=9.3, 13.5 Hz); 2.85 (dd, 1H, PhCHH,J=5.4, 13.5 Hz); 4.11 (q, 2H, CH ₂CH₃, J=7.0 Hz) 4.26-4.47 (m, 1H,NHCH); 5.82 (d, 1H, COCH, J=15.7 Hz); 6.85 (dd, 1H, COCHCH, J=5.4, 15.7Hz); 7.09-7.42 (m, 5H, Ph).

EXAMPLE 4 4R-4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid (4)

4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid ethyl ester (3)(2.15 g, 6.73 mmol) is hydrolyzed with NaOH 1N in MeOH/water. Thereaction is immediate. HCl 2N is then added dropwise until totalprecipitation of the product which is collected by filtration on aBuckner funnel washing with water.4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid (4) is obtained asa white solid (1.75 g, 6.06 mmol, yield=90%). HPLC (method A): Rt=10.05min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.30 (s, 9H, C(CH₃)₃); 2.71 (m, 1H,PhCHH); 2.83 (dd, 1H, PhCHH, J=6.0, 13.5 Hz); 3.97-4.43 (m, 1H, NHCH);5.73 (d, 1H, COCH, J=15.7 Hz); 6.77 (dd, 1H, COCHCH, J=5.4, 15.7 Hz);7.08-7.42 (m, 5H, Ph).

EXAMPLE 5 4R-4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid2,5-dioxo-pyrrolidin-1-yl ester (5)

To a solution of 4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid(4) (1.50 g, 5.14 mmol, 1.0 eq.) in THF (25 mL) kept at 0° C. using anice bath are added N-hydroxysuccinimide (0.59 g, 5.14 mmol, 1.0 eq.) andsubsequently N,N′-dicyclohexylcarbodiimide (1.06 g, 5.14 mmol, 1.0 eq.)in three parts in 10 minutes. The resulting mix is left under magneticstirring at room temperature for 12 hours. The solid dicyclohexylureaformed is eliminated by filtration washing with THF. The solvent is thenremoved by distillation under reduced pressure to give4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid2,5-dioxo-pyrrolidin-1-yl ester (5) as a spongy white solid (1.94 g,5.00 mmol, yield=97%). HPLC (method A): Rt=10.56 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.32 (s, 9H, C(CH₃)₃); 2.70-2.77 (m,1H,PhCHH); 2.83 (s, 4H, CH₂CH₂); 2.94 (dd,1H, PhCHH, J=5.3, 13.6 Hz);4.32-4.71 (m, 1H, NHCH); 6.14 (d, 1H, COCH═CH, J=15.6 Hz); 7.06-7.49 (m,5H, Ph+1H, COCH═CH).

EXAMPLE 61R-[1-Benzyl-3-(3-dimethylamino-propylcarbamoyl)-allyl]-carbamic acidtert-butyl ester (6)

3-dimethylaminopropylamine (0.071 mL, 0.566 mmol, 1.1 eq.) is added to asolution of 4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid2,5-dioxo-pyrrolidin-1-yl ester (5) (0.200 g, 0.515 mmol, 1.0 eq.) inanhydrous THF (6.0 mL) and the resulting mixture left under magneticstirring at room temperature for 3 hours. AcOEt (5 mL) and a 10%solution of NaHCO₃ (10 mL) are added and the phases separated. Theorganic phase is then washed with water (10 mL) and brine (10 mL), driedon Na₂SO₄, and then washed with filtered water and the solvent removedby evaporation under reduced pressure. The product[1-Benzyl-3-3-dimethylamino-propylcarbamoyl)-allyl]-carbamic acidtert-butyl ester (6) obtained is used in the subsequent reaction withoutfurther purification.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.31 (s, 9H, C(CH₃)₃); 1.52 (t, 2H, NCH₂CH ₂, J=7.0 Hz); 2.10 (s, 6H, N(CH₃)₂); 2.18 (t, 2H, NCH₂, J=7.2 Hz);2.68-2.85 (m, 2H, CONCH₂); 2.95-3.19 (m, 2H, PhCH ₂); 4.16-4.43 (m, 1H,NHCH); 5.88 (d, 1H, COCH, J=15.4 Hz); 6.56 (dd, 1H, COCHCH, J=5.7, 15.4Hz); 7.07 (d, 1H, OCONH, J=8.7 Hz); 7.13-7.40 (m, 5H, Ph); 7.93-8.11 (m,1H, NH).

Analogously, the following was prepared:

EXAMPLE 71R-[1-Benzyl-3-(2-dimethylamino-ethylcarbamoyl)-allyl]-carbamic acidtert-butyl ester (7)

The product is used in subsequent reactions without furtherpurification.

HPLC (method A): Rt=7.09 min.

EXAMPLE 8 4R-4-Amino-5-phenyl-pent-2-enoic acid(3-dimethylamino-propyl)-amide (8)

[1-Benzyl-3-(3-dimethylamino-propylcarbamoyl)-allyl]-carbamic acidtert-butyl ester (6) is deprotected by treatment with a 4N solution ofHCl in dioxane for 15 minutes at room temperature. The solvent is thenremoved by evaporation under reduced pressure. The solid obtained istriturated with Et₂O and isolated by filtration washing with Et₂O.4-Amino-5-phenyl-pent-2-enoic acid (3-dimethylamino-propyl)-amide (8) isobtained as a clear yellow solid. HPLC (method A): Rt=3.89 min.

EXAMPLE 9

4R-4-Amino-5-phenyl-pent-2-enoic acid (2-dimethylamino-ethyl)-amide (9)is obtained analogously starting from the derivative (7). HPLC (methodA): Rt=3.55 min.

Synthesis Diagram for Compounds 16, 17 and 19

EXAMPLE 10 4S-4-tert-Butoxycarbonylamino-5-phenyl-pentanoic acid ethylester (10)

4-tert-Butoxycarbonylamino-5-phenyl-pent-2-enoic acid ethyl ester (3) isreduced to the double bond by hydrogenation (static atmospheric pressureof H₂, Pd/C at 10%), according to a procedure known to those skilled inthe art, to give 4-tert-Butoxycarbonylamino-5-phenyl-pentanoic acidethyl ester (10) (2.10 g, 6.53 mmol) as white sold that is utilized inthe subsequent reactions without further purification. HPLC (method A):Rt=11.66 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.15 (t, 3H, CH₂ CH ₃, J=7.1 Hz); 1.32 (s,9H, C(CH₃)₃); 1.44-1.60 (m, 1H, COCH₂CHH); 1.60-1.80 (m, 1H, COCH₂CHH);2.18-2.40 (m, 2H, COCH₂); 2.60-2.74 (m, 2H, PhCH ₂); 3.52-3.72 (m, 1H,NHCH); 4.00 (q, 2H, CH ₂CH₃, J=7.1 Hz); 6.71 (d, 1H, NH, J=10.0 Hz);7.11-7.40 (m, 5H, Ph).

EXAMPLE 11 4S-4-tert-Butoxycarbonylamino-5-phenyl-pentanoic acid (11)

4-tert-Butoxycarbonylamino-5-phenyl-pentanoic acid ethyl ester (10)(2.00 g, 6.22 mmol) is hydrolyzed with NaOH 1N in MeOH/water. Thereaction is immediate. HCl 2N is then added dropwise until totalprecipitation of the product which is collected by filtration on aBuckner funnel washing with water.4-tert-Butoxycarbonylamino-5-phenyl-pentanoic acid (11) is obtained as awhite solid (1.66 g, 5.66 mmol, yield=91%). HPLC (method A): Rt=9.28min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.32 (s, 9H, C(CH₃)₃); 1.46-1.54 (m, 1H,COCH₂CHH); 1.62-1.70 (m, 1H, COCH₂CHH); 2.20 (m, 2H, COCH₂); 2.65 (m,2H, PhCH ₂); 3.60 (m, 1H, NHCH); 6.72 (d, 1H, NH, J=6.7 Hz); 7.16-7.29(m, 5H, Ph); 11.99 (bs, 1H, OH);

EXAMPLE 12

4S-8-tert-Butoxycarbonylamino-5-phenyl-pentanoic acid2,5-dioxo-pyrrolidin-1-yl ester (12) is obtained by reaction of (11)(1.40 g, 4.77 mmol, 1.0 eq.) with DCC (1.08 g, 5.24 mmol, 1.1 eq) andNHS (0.55 g, 4.77 mmol, 1.0 eq.) following the procedure indicated inExample 5. The product is obtained as a white solid (1.53 g, 0.419 mmol,yield=88%).

HPLC (method A): Rt=10.39 min.

With an analogous procedure to the one described in Example 6 thecompounds 13-15 are obtained by reaction of (12) with suitable amine.

EXAMPLE 13

1S-[1-Benzyl-3-(3-dimethylamino-propylcarbamoyl)-propyl]-carbamic acidtert-butyl ester (13) is obtained as a very pale yellow oil. HPLC(method A): Rt=6.77 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.32 (s, 9H, C(CH₃)₃); 1.45-1.75 (pseudot+m, 2H+2H, NCH₂ CH ₂+COCH₂ CH ₂); 2.00-2.17 (m, 2H, COCH₂); 2.25 (s,6H, N(CH₃)₂); 2.32-2.46 (m, 2H, (CH₃)₂NCH ₂); 2.65 (d, 2H, CONCH ₂,J=6.8 Hz); 3.03 (q, 2H, PhCH ₂, J=6.2 Hz); 3.45-3.65 (m, 1H, NHCH); 6.70(d, 1H, OCONH, J=8.8 Hz); 7.11-7.33 (m, 5H, Ph); 7.74-7.90 (m, 1H, NH).

EXAMPLE 14

1S-[1-Benzyl-3-(2-dimethylamino-ethylcarbamoyl)-propyl]-carbamic acidtert-butyl ester (14) is obtained as a very pale yellow oil. HPLC(method A): Rt=6.45 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.32 (s, 9H, C(CH₃)₃); 1.41-1.71 (m, 2H,COCH₂ CH ₂); 1.94-2.11 (m, 2H, COCH₂); 2.11 (s, 6H, N(CH₃)₂); 2.23 (t,2H, J=6.8 Hz, (CH₃)₂NCH ₂); 2.65 (d, 2H, CONCH ₂, J=6.8 Hz); 3.09(pseudo q, 2H, PhCH ₂, J=6.4 Hz); 3.44-3.66 (m, 1H, NHCH); 6.68 (d, 1H,OCONH, J=8.7 Hz); 7.10-7.37 (m, 5H, ArH); 7.61-7.78 (m, 1H, NH).

EXAMPLE 15

1S-[1-Benzyl-4-(4-benzyl)-piperidin-1-yl)-4-oxo-butyl]-carbamic acidtert-butyl ester (15) is obtained as a white solid from purification byflash chromatography using chloroform as eluent.

HPLC (method A): Rt=12.98 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 0.90-1.12 (m, 2H, Hc); 1.32 (s, 9H,C(CH₃)₃); 1.38-1.65 (m, 2H, COCH₂ CH ₂); 1.56-1.85 (m, 2H+2H, COCH₂+Hd);2.26 (m, 1H, Ha); 2.38(m, 1H, He); 2.48 (d, 2H, PhCH ₂CHe, J=5.4 Hz);2.66 (m, 2H, PhCH₂); 2.87 (t, 1H, Hb′, J=12.3 Hz); 3.59 (m, 1H, NHCH);3.71-3.76 (m, 1H, Ha); 4.30-4.35 (m, 1H, Ha′); 6.72 (d, 1H, CONH, J=8.7Hz); 7.16-7.20 (m, 5H, ArH); 7.22-7.40 (m, 5H, ArH).

With an analogous procedure to the one described in Example 8 thecompounds 16 and 17 are obtained by deprotection reaction of 13 and 14.

EXAMPLE 16

4S-4-Amino-5-phenyl-pentanoic acid (3-dimethylamino-propyl)-amidehydrochloride (16) which is used in subsequent reactions without furtherpurification. HPLC (method A): Rt=3.69 min.

EXAMPLE 17

4S-4-Amino-5-phenyl-pentanoic acid (2-dimethylamino-ethyl)-amidedi-hydrochloride (17) which is used in subsequent reactions withoutfurther purification. HPLC (method A): Rt=3.45 min.

EXAMPLE 18

4S-4-Amino-1-(4-benzyl-piperidin-1-yl)-5-phenyl-pentan-1-onehydrochloride (18) which is used in subsequent reactions without furtherpurification.

MS (m/z): 351.5 (MH⁺). HPLC (method A): Rt=8.45 min

EXAMPLE 19 1S-Benzyl-4-(4-benzyl-piperidin-1-yl)-butylamine (19)

The product described in the Example 18 (0.30 g, 0.77 mmol, 1.0 eq.) isreduced to the amide bond with LiAlH₄ (0.147 g, 3.88 mmol, 5.0 eq.) inanhydrous THF (10 mL) by reflux for one night. The reaction is quenchedby cooling the flask in an ice bath and carefully adding first ice andthen water. Et₂O (20 mL) and solid NaOH are then added in order tosaturate the aqueous solution and the resulting biphasic mixture isstirred at room temperature for about 30 minutes. The various aluminiumsalts formed are eliminated by filtration on Celite® washing both withwater and with ether. The solution obtained is then transferred to aseparatory funnel and the phases separated. The organic phase is washedwith water (20 mL) and brine (20 mL), dried on Na₂SO₄, filtered and thesolvent removed by evaporation under reduced pressure. The oily productobtained is treated with HCl 4N in 1,4-dioxane to give1-Benzyl-4-(4-benzyl-piperidin-1-yl)-butylamine (19) as pale yellowsolid (0.23 g, 0.56 mmol, yield=73%) which is used in subsequentreactions without further purification.

MS (m/z): 337.8 (MH⁺). HPLC (method A): Rt=5.78 min.

Synthesis Diagram for Compounds 27, 28 and 29

EXAMPLE 20 4-(Tetrahydro-pyran-4-ylmethyl)-piperazine-1-carboxylic acidbenzyl ester (20)

Piperazine-1-carboxylic acid benzyl ester (1.03 g, 4.68 mmol, 1.0 eq.)and 4-tetraidropiranil aldeide (0.8 mg, 7.0 mmol, 1.5 eq.) are dissolvedin 20 ml of anhydrous DCM. Na(OAc)₃BH (1.48 g, 7.0 mmol, 1.5 eq.) areadded to this opalescent solution. The reaction is left under magneticstirring and under a nitrogen atmosphere at room temperature for 2hours. When the reaction is completed the solvent is removed byevaporation under reduced pressure. AcOEt (20 mL) and a 1N solution ofNaOH (20 mL) are added and the biphasic system transferred to aseparatory funnel. The phases are separated and the organic phase iswashed with water and brine, dried on Na₂SO₄, filtered and the solventremoved by evaporation under reduced pressure.

4-(Tetrahydro-pyran-4-ylmethyl)-piperazine-1-carboxylic acid benzylester (20) is obtained as a colourless oil (1.3 g, 4.08 mmol, yield=87%)

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.10 (qd, 2H, Hc, J=6.3, 13.5 Hz); 1.59(d, 2H, Hd, J=12.6 Hz); 1.72 (m, 1H, He); 2.30 (m, 4H, Hh); 2.63 (m, 2H,Hf); 3.23-3.37 (m, 4H+2H, Hg+Hb), 3.80-3.84 (m, 2H, Ha), 5.07 (s, 2H,PhCH₂); 7.31-7.40 (m, 5H, ArH).

An analogous procedure to the one described in Example 20 is used toprepare compound 20 obtained as a colourless oil with a yield=85%.

EXAMPLE 21 4-Tetrahydro-pyran-4-yl)piperazine-1-carboxylic acid benzylester (21)

HPLC (method A): Rt=5.68 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.19 (qd, 2H, Hc, J=6.3, 13.5 Hz); 1.69(d, 2H, Hd, J=12.6 Hz); 2.36-2.58 (m, 4H+1H, Hf+He); 3.15-3.53 (m,4H+2H, Hg+Hb); 3.93 (m, 2H, Ha); 5.07 (s, 2H, PhCH₂); 7.27-7.45 (m, 5H,ArH).

EXAMPLE 22 1-(Tetrahydro-pyran-4-ylmethyl)-piperazine di-hydrochloride

The product of Example 20 is deprotected by hydrogenation (H₂, Pd/C at10%/o), according to a procedure known to those skilled in the art, togive 1-(Tetrahydro-pyran-4-ylmethyl)-piperazine which through treatmentwith HCl 4N in 1,4-dioxane and subsequent elimination of the solventunder reduced pressure produces the corresponding dichlorhydrate (22) asa white solid (1.03 g, 4.00 mmol, yield=98%).

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.12-1.32 (m, 2H, Hc); 1.70-1.80 (m, 2H,Hd); 2.03 (m, 1H, He); 3.06 (m, 2H, Hf); 3.29 (t, 2H, Hb, J=11.4 Hz);3.40-3.80 (m, 4H+4H, Hg÷Hh); 3.81-3.87 (m, 2H, Ha); 9.6 (bs, 2H, ⁺NH₂);11.2 (bs, 1H, ⁺NH)

EXAMPLE 23

An analogous procedure to the one described in Example 22 is used toprepare compound 23 starting from 21

1-(Tetrahydro-pyran-4-yl)-piperazine di-hydrochloride (23) is obtainedas a white solid (0.4 g, 1.64 mmol, yield=95%).

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.62-1.83 (m, 2H, Hc), 1.93-2.08 (m, 2H,Hd); 3.30 (t, 2H, Hb, J=11.4 Hz); 3.38-3.60 (m, 4H 4H, Hg+Hh); 3.61-3.81(m, 1H, He); 3.95-4.03 (m, 2H, Ha); 9.6 (bs, 2H, ⁺NH₂); 12.0 (bs, 1H,⁺NH).

EXAMPLE 24

An analogous procedure to the one described in Example 6 is used toprepare compounds 24-26 starting from 11 and/or 22 or 23 or 4-piperidinethanol.

1S-{1-Benzyl-4-oxo-4-[4-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-butyl}-carbamicacid tert-butyl ester (24) is obtained as a yellow oil and used in thesubsequent reactions without further purification.

HPLC (method A): Rt=7.21 min. MS (m/z): 460.3 (MH⁺).

EXAMPLE 25

1S-{1-Benzyl-4-oxo-4-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-butyl}-carbamicacid tert-butyl ester (25) is obtained as a yellow oil and used in thesubsequent reactions without further purification.

HPLC (method A): Rt=7.10 min. MS (m/z): 446.8 (MH⁺).

EXAMPLE 26

1S-{1-Benzyl-4-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-oxo-butyl}-carbamicacid tert-butyl ester (26) is obtained as a yellow oil and used in thesubsequent reactions without further purification.

HPLC (method A): Rt=8.75 min.

An analogous procedure to the one described in Example 8 is used toprepare compounds 27-29 starting from 24-26

EXAMPLE 27

4S-4-Amino-5-phenyl-1-[4-tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-pentan-1-onedi-hydrochloride (27) is obtained as a pale yellow solid and used in thesubsequent reactions without further purification.

HPLC (method A): Rt=4.14 min. MS (m/z): 360.1 (MH⁺).

EXAMPLE 28

4S-4-Amino-5-phenyl-1-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-pentan-1-onedi-hydrochloride (28) is obtained as a pale yellow solid and used in thesubsequent reactions without further purification.

HPLC (method A): Rt=4.06 min. MS (m/z): 346.9 (MH⁺).

EXAMPLE 29

4S-4-Amino-1-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-5-phenyl-pentan-1-onehydrochloride (29) is obtained as a white solid and used in thesubsequent reactions without further purification.

HPLC (method A): Rt=5.06 min. MS (m/z): 304.9 (MH⁺).

An analogous procedure to the one described in Example 19 is used toprepare compounds 30 and 31 starting from 27 and 29.

Synthesis Diagram for Compounds 30, 31 and 37

EXAMPLE 30

1S-1-Benzyl-4-[4-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-butylaminetri-hydrochloride (30) is obtained as a yellow oil and used insubsequent reactions without further purification. MS (m/z): 346.2(MH⁺).

EXAMPLE 31

2-[1-(4S-4-Amino-5-phenyl-pentyl)-piperidin-4-yl]-ethanoldi-hydrochloride (31) is obtained as a yellow oil and used in subsequentreactions without further purification. MS (m/z): 291.1 (MH⁺).

EXAMPLE 32 4-(Tetrahydro-pyran-4-carbonyl)-piperazine-1-carboxylic acidbenzyl ester (32)

A mixture of tetrahydro-pyran-4-carboxylic acid (0.477 g, 2.27 mmol, 1.0eq.) EDCA (0.480 g, 2.50 mmol, 1.1 eq.) and HOBt (0.340 g, 2.50 mmol,1.1 eq.) in THF/DMF (8 mL/2 mL) is kept under magnetic stirring at roomtemperature for about 1 hour.

Piperazine-1-carboxylic acid benzyl ester (0.438 mL, 2.27 mmol, 1.0 eq.)is then added and the resulting reaction mixture is left to react for 14hours. AcOEt (10 mL) and a 10% solution of NaHCO₃ (10 mL) are added andthe phases are separated. The organic phase is then washed with water(2×10 mL) and brine (10 mL), dried on Na₂SO₄, filtered and the solventremoved by evaporation under reduced pressure.4-(Tetrahydro-pyran-4-carbonyl)-piperazine-1-carboxylic acid benzylester (32) is obtained as an ivory coloured solid (0.613 g, 1.85 mmol,yield=81%) which does not require further prcation. HPLC (method A):Rt=7.71 min.

An analogous procedure to the one described in Example 22 is used toprepare compound 33 starting from 32.

EXAMPLE 33

Piperazin-1-yl-(tetrahydro-pyran-4-yl)-methanone (33) is obtained as acolourless oil that does not require further purification. MS (m/z):199.7 (MH⁺).

EXAMPLE 34 1S-[1-Benzyl-3-(methoxy-methyl-carbamoyl)-propyl]-carbamicacid tert-butyl ester (34)

A solution of O,N-dimethyl-hydroxylamine hydrochloride (0.075 g, 0.77mmol, 1.0 eq.) and DTPEA (0.131 mL, 0.77 mmol, 1.0 eq.) in DMF (2 mL) isadded to a solution of 12 (0.300 g, 0.77 mmol, 1.0 eq.) in DMF (8 mL)and the resulting mixture is kept under magnetic stirring a 100° C. forone night. AcOEt (10 mL) and a 10% solution of NaHCO₃ (10 mL) are addedand the phases are separated. The organic phase is then washed withwater (2×10 mL) and brine (10 mL), dried on Na₂SO₄, filtered and thesolvent removed by evaporation under reduced pressure.[1-Benzyl-3-(methoxy-methyl-carbamoyl)-propyl]-carbamic acid tert-butylester (34) is used in the subsequent reaction without furtherpurification.

MS (m/z): 337.1 (MH⁺).

EXAMPLE 35 1S-(1-Benzyl-4-oxo-butyl)-carbamic acid tert-butyl ester (35)

The product obtained from the previous reaction (34, Weinreb amide)(0.150 g, 0.446 mmol, 1.0 eq.) is reduced to aldehyde treating withLiAlH₄ (0.084 g, 2.230 mmol, 5.0 eq.) in THF (10 mL) at 4° C. for 15minutes. Et₂O (5 mL) and a 5% aqueous solution of KHSO₄ are then addedand the phases separated. The aqueous phase is washed with Et₂O (2×5mL). The recombined organic phase is then washed with water (10 mL) andbrine (10 mL), dried on Na₂SO₄, filtered and about half of the solventremoved by evaporation under reduced pressure.(1-Benzyl-4-oxo-butyl)-carbamic acid tert-butyl ester (35) is notisolated, but used as ether solution.

EXAMPLE 361S-{1-Benzyl-4-[4-(tetrahydro-pyran-4-carbonyl)-piperazin-1-yl]-butyl}-carbamicacid tert-butyl ester (36)

Assuming a quantitative yield for the previous reaction, a reductiveamination reaction is carried out between aldehyde 35 (0.446 mmol) asether solution and amine 33 (0.044 g, 0.223 mmol, 0.5 eq.) in thepresence of Na(OAc)₃BH (0.122 g, 0.580 mmol, 1.3 eq.) adding DCM (3 mL).The mixture obtained is left under magnetic stirring at room temperaturefor 14 hours. A 1N aqueous solution of NaOH (5 mL) is then added and thephases separated. The organic phase is then washed with water (10 mL)and brine (10 mL), dried on Na₂SO₄, filtered and the solvent removed byevaporation under reduced pressure.{1-Benzyl-4-[4-(tetrahydro-pyran-4-carbonyl)-piperazin-1-yl]-butyl}-carbamicacid tert-butyl ester (36) is obtained as a colourless oil that does notrequire further purification.

MS (m/z): 460.3 (MH⁺).

EXAMPLE 37

An analogous procedure to the one described in Example 8 is used toprepare compound 37 starting from 36.

4S-[4-(4-Amino-5-phenyl-pentyl)-piperazin-1-yl]-(tetrahydro-pyranyl)-methanonedi-hydrochloride (37) is obtained as a yellow solid and used in thesubsequent reactions without further purification. MS (m/z): 360.1(MH⁺).

Synthesis Diagram for Compound 45

EXAMPLE 38 4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butylester (37)

A mixture of 4-piperidin ethanol (2.0 g, 15 mmol, 1.0 eq.) and t-butyldicarbonate (3.87 mL, 18.5 mmol, 1.2 eq.) in anhydrous THF (80 mL) iskept under stirring at room temperature for one night. The solvent isthen removed by evaporation under reduced pressure and the raw productobtained purified by flash chromatography using AcOEt: petroleum ether60:40 as eluent mixture. 4-(2-Hydroxy-ethyl)-piperidine-1-carboxylicacid tert-butyl ester (37) is obtained as a colourless oil (3.1 g, 13.4mmol, yield=87%)

HPLC (method A): Rt=7.92 min.

H¹ NMR (δ, CDCl₃-d₃, 300 MHz): 1.14 (dq, 2H, Hf, J=6.3, 13.5 Hz); 1.47(s, 9H, C(CH₃)₃); 1.55 (pt, 2H, Hc, J=6.3 Hz); 1.50-1.65 (m, 1H, Hc);1.69 (d, 2H, Hd, J=13.2 Hz); 1.89 (s, 1H, OH); 2.71 (td, 2H, Hb, J=2.1,12.9 Hz); 3.73 (t, 2H, Hg, J=6.3 Hz); 4.10 (m, 2H, Ha).

EXAMPLE 39 4-(2-Iodo-ethyl)-piperidine-1-carboxylic acid tert-butylester (39)

A solution of PPh₃ (1.20 g, 4.60 mmol, 1.3 eq.) and imidazole (0.32 g,4.60 mmol, 1.3 eq.) temperature. A solution of 38 (0.81 g, 3.54 mmol,1.0 eq.) in DCM (5 mL) is added and the resulting reaction mixture keptunder stirring at room temperature for one night. Et₂O (100 mL) andwater (50 mL) are added, the biphasic mixture transferred to aseparatory funnel and the phases separated. The organic phase issubsequently washed with a saturated solution of NaHCO₃ (100 mL), a 5%aqueous solution of Na₂SO₃ (100 mL) and brine (100 mL), dried on Na₂SO₄,filtered and the solvent removed by evaporation under reduced pressure.The raw product obtained is purified by flash chromatography usingpetroleum ether. AcOEt 90:10 as eluent mixture.4-(2-Iodo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester 39 isobtained as a colourless oil (1.08 g, 3.19 mmol, yield=90%).

HPLC (method A): Rt=13.38 min.

H¹ NMR (δ, DMSO-d₆, 300 MHz): 1.04 (dq, 2H, Hf, J=4.3, 11.5 Hz); 1.39(s, 9H, C(CH₃)₃); 1.46-1.56 (m, 1H, He); 1.62 (pd, 2H, Hc, J=14.1 Hz);1.72 (q, 2H, Hd, J=6.9 Hz); 2.68 (m, 2H, Hg); 3.30 (m, 2H, Hb); 3.91 (m,2H, Ha).

EXAMPLE 40[2-(1-tert-Butoxycarbonyl-piperidin-4-yl)-ethyl]-triphenyl-phosphoniumiodide (40)

A solution of 39 (0.696 mg, 2.05 mmol, 1.0 eq.) and PPh₃ (0.592 g, 2.259mmol, 1.1 eq.) in CH₃CN (5 mL) is kept under stirring at the refluxtemperature of the solvent for 2 days. The reaction mixture is thencooled and the solvent removed by evaporation under reduced pressure.The raw white solid obtained, consisting of the desired product and ofthe excess PPh₃ is left under stirring in Et₂O (10 mL) for 10 minutes.All the excess PPh₃ is solubilized whereas the white residue iscollected by filtration washing with Et₂O.[2-(1-tert-Butoxycarbonyl-piperidin-4-yl)-ethyl]-triphenyl-phosphoniumiodide (40) is obtained as a white solid (0.914 g, 1.52 mmol,yield=74%).

HPLC (method A): Rt=9.19 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 0.96-1.10 (m, 2H, Hf); 1.38 (s, 9H,C(CH₃)₃); 1.45-1.60 (m, 2H+1H, Hc+He); 1.73 (d, 2H, Hd, J=12.0 Hz); 2.66(m, 2H, Hg); 3.50-3.65 (m, 2H, Hb); 3.94 (m, 2H, Ha); 7.78-7.83 (m, 12H,ArH); 7.84-7.91 (m, 3H, ArH).

EXAMPLE 42 2R-3-Phenyl-2-(trityl-amino)-propionaldehyde (42)

An analogous procedure to the one described in Example 2 is used toprepare compound 42 starting from 3-Phenyl-2-(trityl-amino)-propan-1-ol(41).

3-Phenyl-2-(trityl-amino)-propionaldehyde (42) is obtained as a verypale yellow solid (0.650 g, 1.66 mmol, yield=97%).

H¹ NMR (δ,DMSO-d₆, 300 MHz): 2.66 (m, 2H, PhCH ₂); 3.18-3.25 (m, 1H,NHCHCO); 3.63 (d, 1H, NH, J=9.6 Hz); 7.15-7.34 (20 H, m, ArH); 8.72 (s,1H, COH).

EXAMPLE 434-[4R-5-Phenyl-4-(trityl-amino)-pent-2-enyl]-piperidine-1-carboxylicacid tert-butyl ester (43)

To a suspension of 40 (0.614 g, 1.02 mmol, 1.0 eq.) in anhydrous THF (3mL) kept under stirring and under nitrogen atmosphere at roomtemperature is added NaHMDS 1M in THF (1 mL, 1.02 mmol, 1.0 eq.). Afterabout 10 minutes the salt dissolves completely and the solution assumesa bright orange colour. The mixture is cooled to −40° C. and a solutionof 42 (0.600 g, 1.53 mmol, 1.5 eq.) in anhydrous THF (3 mL) kept at −40°C. is added and the resulting reaction mixture kept under stirring undernitrogen atmosphere allowing the temperature to rise slowly to roomtemperature. Et₂O (10 mL) and brine (10 mL) are added and the phasesseparated. The organic phase is further washed with brine (10 mL) driedon Na₂SO₄, filtered and the solvent removed by evaporation under reducedpressure. The raw product obtained is purified by flash chromatographyusing as eluent mixture petroleum ether. AcOEt from 99:1 to 95:5.4-[5-Phenyl-4-(trityl-amino)-pent-2-enyl]-piperidine-1-carboxylic acidtert-butyl ester (43) is obtained as a colourless oil (0.200 g, 0.34mmol, yield=34%). HPLC (method A): Rt=11.65 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 0.36-1.3 (m, 2H+5H, CH₂(Pip)+CH(CH ₂)₂);1.38 (s, 9H, C(CH₃)₃); 2.04-2.18 (m, 2H, PhCH₂); 2.41 (m, 2H, N(CHH)₂);3.3 (m, 1H, NHCH); 3.72 (m, 2H, N(CHH)₂); 4.97 (m, 1H, NHCHCHCH); 5.29(t, 1H, NHCHCH, J=10.4 Hz); 6.78 (d, 2H, ArH, J=7.2 Hz); 7.03-7.22 (m,6H, ArH); 7.22-7.31 (m, 6H, ArH); 7.42-7.53 (m, 6H, ArH).

An analogous procedure to the one described in Example 10 is used toprepare compound 44 starting from 43.

EXAMPLE 44

4-[4R-5-Phenyl-4-(trityl-amino)-pentyl]-piperidine-1-carboxylic acidtert-butyl ester (44) is obtained as a yellow oil and used in thesubsequent reaction without further purification.

MS (m/z): 590.1 (MH⁺). HPLC (method A): Rt=11.68 min.

EXAMPLE 45 4-(4R-4-Amino-5-phenyl-pentyl)-piperidine-1-carboxylic acidtert-butyl ester (45)

The raw reaction product 44 (0.340 g) is treated for 15 minutes with a1% solution of TFA in DCM (5 mL). Two drops of water are then added andthe solution left under stirring for a further 10 minutes. NaOH 2M (5mL) is added and the phases separated. The aqueous phase is washed withDCM (2×10 mL) and the recombined organic phase dried on Na₂SO₄, filteredand the solvent removed by evaporation under reduced pressure.4-(4-Amino-5-phenyl-pentyl)-piperidine-1-carboxylic acid tert-butylester (45) is obtained raw as a yellow oil and used in the subsequentreaction without further purification.

MS (m/z): 347.2 (MH⁺), 291 (-tBu), 247.2 (-BOC). HPLC (method B):Rt=3.96 min.

General Procedure for Coupling between Oxazolone and the Various Amines.

To a solution of2-(benzo[b]thiophen-2-yl)-4-cyclopentyl-1,3-oxazolin-5-one (1.0 eq.)(Examples 46-50) or2-(6-methyl-benzo[b]thiophen-2-yl)-4-cyclopentyl-1,3-oxazolin-5-one (1.0eq.) (Examples 51-57) in DMF (10 mL) are added a solution of amine (1.0eq.) and DIPEA (2.2 eq.) in DMF (3 mL) and the reaction mixture obtainedis left under magnetic stirring at room temperature for 10 hours. AcOEt(10 mL) and a 10% aqueous solution of NaHCO₃ are added and the phasesseparated. The organic phase is then washed with brine (10 mL) dried onNa₂SO₄, filtered and the solvent removed by evaporation under reducedpressure. The raw product thus obtained is purified by flashchromatography using CHCl₃:MeOH 98:2 as eluent system. The followingproducts were obtained with this procedure.

EXAMPLE 46 (R) Benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-3-(3-dimethylamino-propylcarbamoyl)-allylcarbamoyl]-cyclopentyl)-amide(46)

MS (m/z): 547.9 (MH⁺). HPLC (method A): Rt=7.78 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.50-1.75 (m, 4H, cyclopen.); 1.87-2.07 (m,2H+4H, CH₂ CH ₂CH₂+cyclopen.); 2.12 (s, 6H, N(CH₃)₂); 2.20 (m, 2H,NCH₂); 2.79 (m, 2H, PhCH₂); 3.10 (m, 2H, CONCH₂); 4.64 (m, 1H, NHCH);5.86 (d, 1H, NHCOCH, J=15.4 Hz); 6.56 (dd, 1H, NHCHCH, J=5.8, 15.4 Hz);7.06-7.20 (m, 5H, ArH); 7.46 (m, 1H+1H, C(6)H+C(5)H); 7.70 (m, 1H,CONHCH₂); 7.79 (m, 1H, NHCH); 7.91-8.07 (m, 1H+1H, C(4)H+C(7)H); 8.26(s, 1H, C(3)H); 8.49 (s, 1H, NH-1Ac6c)

EXAMPLE 47 (R) Benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-3-(2-dimethylamino-ethylcarbamoyl)-allylcarbamoyl]-cyclopentyl}-amide(47)

MS (m/z): 533.85 (MH⁺). HPLC (method A): Rt=7.79 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.50-1.75 (m, 4H, cyclopen.); 1.89-2.10 (m,4H, cyclopen.); 2.13 (s, 6H, N(CH₃)₂); 2.27 (t, 2H, NCH₂, J=6.6 Hz);2.80 (d, 2H, PhCH₂, J=7.2 Hz); 3.18 (m, 2H, CONCH₂); 4.57-4.75 (m, 1H,NHCH); 5.90 (d, 1H, NHCOCH, J=15.4 Hz); 6.57 (dd, 1H, NHCHCH, J=5.6,15.4 Hz); 7.08-7.18 (m, 5H, ArH); 7.46 (m, 1H+1H, C(6)H+C(5)H); 7.62 (m,1H, CONHCH₂); 7.70 (m, 1H, NHCH); 7.90-8.08 (m, 1H+1H, C(4)H+C(7)H);8.26 (s, 1H, C(3)H); 8.49 (s, 1H, NH-1Ac6c).

EXAMPLE 48 (S) Benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-3-(3-dimethylamino-propylcarbamoyl)-propylcarbamoyl]-cyclopentyl}-amide(48)

MS (m/z): 549.2 (MH⁺). HPLC (method A): Rt=7.67 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.51-1.75 (m, 2H+2H+4H, NCH₂ CH ₂+CH₂CH₂CO+cyclopen.); 1.85-2.05 (m, 2H+4H, COCH ₂+cyclopen.); 2.07 (s, 6H,N(CH₃)₂); 2.14 (m, 2H, NCH ₂CH₂); 2.63-2.72 (m, 2H, PhCH₂); 2.92-3.03(m, 2H, CONCH₂); 3.91 (m, 1H, NHCH); 7.08-7.23 (m, 5H, ArH); 7.40 (m,1H, NHCH); 7.46 (m, 1H+1H, C(6)H+C(5)H); 7.54 (m, 1H, CONHCH₂);7.90-8.05 (m, 1H+1H, C(4)H+C(7)H); 8.26 (s, 1H, C(3)H); 8.52 (s, 1H,NH-1Ac6c)

EXAMPLE 49

(S) Benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-3-(2-dimethylamino-ethylcarbamoyl)-propylcarbamoyl]-cyclopentyl}-amide(49) obtained as a trifluoroacetate salt through adding a solution ofTFA in DCM and subsequent evaporation of the solvent under reducedpressure.

MS (m/z): 535.3 (MH⁺). HPLC (method A): Rt=7.95 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.40-1.75 (m, 2H+4H, CH ₂CH₂CO+cyclopen.);1.83-2.07 (m, 2H+4H, COCH ₂÷cyclopen.); 2.11 (s, 6H, N(CH₃)₂); 2.18-2.31(m, 2H, (CH₃)₂NCH₂); 2.59-2.76 (m, 2H, PhCH₂); 2.98-3.12 (m, 2H, CONHCH₂); 3.83-3.91 (m, 1H, NHCH); 7.08-7.20 (m, 5H, ArH); 7.38 (m, 1H, NHCH);7.40-7.50 (m, 1H+1H+1H, CONHCH₂+C(6)H+C(5)H); 7.90-8.07 (m, 1H÷1H,C(4)H+C(7)H); 8.25 (s, 1H, C(3)H); 8.51 (s, 1H, NH-1Ac6c).

EXAMPLE 50

(S) Benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-4-(4-benzyl-piperidin-1-yl)-butylcarbamoyl]-cyclopentyl}-amide(50) MS (m/z): 608.3 (MH⁺).HPLC (method A): Rt=9.99 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.20-2.10 (m, 9H+8H+2H+2H,pip.+cyclopen.÷NHCHCH ₂ CH ₂); 2.71-3.09 (m, 2H+2H+2H,PhCH₂+PhCH₂+CH₂N); 3.83-4.17 (m, 1H. NHCH): 6.99-7.64 (m,5H+5H+1H+1H+1H, ArH ArH+NHCH+C(6)H+C(5)H); 7.95 (m, 1H+1H, C(4)H+C(7)H);8.26 (s, 1H, C(3)H); 8.31 (s, 1H, NH-1Ac6c).

EXAMPLE 51

(S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid(1-{1-benzyl-4-oxo-4-[4-tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide(51) obtained as a trifluoroacetate salt through adding a solution ofTFA in DCM and subsequent evaporation of the solvent under reducedpressure.

MS (m/z): 645.3 (MH⁺).HPLC (method A): Rt=8.22 min.

EXAMPLE 52 (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid(1-{1-benzyl-4-oxo-4-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)amide(52)

MS (m/z): 631.2 (MH⁺). HPLC (method A): Rt=8.14 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.18-1.34 (m, 2H, O(CH₂CHH)₂); 1.39-1.89(m, 2H+8H, COCH₂ CH ₂+cyclopen.); 1.89-2.02 (m, 1H, COCHH); 2.02-2.13(m, 1H, COCHH); 2.13-2.39 (m, 2H+4H+1H, O(CH₂CHH)₂+N(CH₂)₂+NCH₂ CH2.44(s, 3H, CH₃); 2.60-2.82 (m, 2H, PhCH₂); 3.16-3.40 (m, 2H+4H,O(CHH)₂+CON(CH₂)₂); 3.83 (dd, 2H, O(CHH)₂, J=3.0, 11.0 Hz); 3.88-4.00(m, 1H, NHCH); 7.11-7.23 (m, 5H, ArH); 7.27 (d, 1H, C(5)H, J=7.4 Hz);7.37 (d, 1H, NHCH, J=8.8 Hz); 7.74-7.86 (m, 1H+1H, C(4)H+C(7)H); 8.18(s, 1H, C(3)H); 8.44 (s, 1H, NH-1Ac6c).

EXAMPLE 53 (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid(1-{1-benzyl-4-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-4-oxo-butylcarbamoyl)-cyclopentyl)-amide(53)

MS (m/z): 576.2 (MH⁺). HPLC (method A): Rt=8.34 min

EXAMPLE 54 (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid(1-{1-benzyl-4-[4-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide(54)

MS (m/z): 631.2 (MH⁺). HPLC (method A): Rt=7.48 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.00-1.21 (m, 2H, O(CH₂CHH)₂); 1.22-1.46(m, 5H); 1.51-1.67 (m, 6H); 1.83-2.08 (m, 6H); 2.08-2.25 (m, 8H+2H,Hpip+O(CH₂CHH)₂); 2.45 (s, 3H, CH₃); 2.61-2.73 (m, 2H, PhCH₂); 3.16-3.29(m, 3H); 3.79-3.83 (m, 2H, O(CHH)₂; 3.94-4.00 (m, 1H, NHCH); 7.12-7.23(m, 5H+1H, ArH+C(5)H); 7.28 (d, 1H, NHCH, J=8.4 Hz); 7.80-7.83 (m,1H+1H, C(4)H+C(7)H); 8.15 (s, 1H, C(3)H); 8.34 (s, 1H, NH-1Ac6c).

EXAMPLE 55

(S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid(1-{1-benzyl-4-[4-(tetrahydro-pyran-4-carbonyl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide(55) obtained as a trifluoroacetate salt through adding a solution ofTFA in DCM and subsequent evaporation of the solvent under reducedpressure.

MS (m/z): 645.2 (MH⁺). HPLC (method A): Rt=7.48 min.

H¹ NMR (δ,DMSO-d₆, 300 MHz): 1.39-1.85 (m, 15H); 1.93 (m, 1H); 2.13 (m,1H); 2.45 (s, 3H, CH₃); 2.45 (s, 3H, CH₃); 2.72 (d, 2H, PhCH₂, J=6.8Hz); 3.00-3.14 (m, 6H); 3.38-3.43 (m, 5H); 3.83-4.43 (m, 2H÷H,O(CHH)₂+NHCH); 7.12-7.23 (m, 5H, ArH); 7.29 (d, 1H, C(5)H), J=8.0 Hz);7.44 (d, 1H, NHCH, J=8.8 Hz); 7.78-7.85 (m, 1H+1H, C(4)H+C(7)H); 8.23(s, 1H, C(3)H); 8.54 (s, 1H, NH-1Ac6c); 9.61 (bs, 1H, HN⁺).

EXAMPLE 56 (S)4-[4-({1-[(6-Methyl-benzo[b]thiophene-2-carbonyl)-amino]-cyclopentanecarbonyl}-amino)-5-phenyl-pentyl]-piperidine-1-carboxylic acidtert-butyl ester (56)

MS (m/z): 632.9 (MH⁺). HPLC (method A): Rt=8.89 min.

EXAMPLE 57

An analogous procedure to the one described in Example 8 is used toprepare compound 57 starting from 56.

(S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid[1-(1-benzyl-4-piperidin-4-yl-butylcarbamoyl)-cyclopentyl]-amide (57).MS(m/z): 532.8 (MH⁺).

EXAMPLE 58

An analogous procedure to the one described in Example 20 is used toprepare compound 58 starting from 57 and 4-tetrahydropyranyl aldehyde.

(S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid(1-{1-benzyl-4-[1-(tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-butylcarbamoyl}-cyclopentyl)-amide(58) obtained as a trifluoroacetate salt through adding a solution ofTFA in DCM and subsequent distillation of the solvent under reducedpressure.

MS (m/z): 630.3 (MH⁺). HPLC (method A): Rt=9.06 min.

Synthesis Diagram for 62

EXAMPLE 59 (R)4-[2-(2-Amino-3-phenyl-propoxy)-ethyl]-piperidine-1-carbamic acidtert-butyl ester (59)

To a solution in anhydrous THF (100 mL), distilled on LiAlH₄, ofD-phenyl alaninol (2.00 gr, PM=151, 13.24 mmol) is added potassiumhydride (530 mg, PM=40, 13.2 mmol). The solution is left for two hoursunder stirring and under nitrogen at room temperature. The4-(2-lodo-ethyl)-piperidine-1-carbamic acid tert-butyl ester 39 (4.5 gr,PM=339, 13.24 mmol), dissolved in 50 mL of anhydrous THF is then addedthrough a dropping funnel. The reaction is left under stirring at roomtemperature for 12 hours. The solution is concentrated at reducedpressure, transferred to a separatory funnel with ethyl acetate and theorganic phase is washed with NaOH 2N, brine and is dried on anhydrousNa₂SO₄. The raw reaction product is purified on a flash column (CHCl₃95/MeOH 5) obtaining 650 mg of4-[2-(2-Amino-3-phenyl-propoxy)-ethyl]-piperidine-1-carbamic acidtert-butyl ester 59 (1.79 mmol, PM=362, Yield=14%)

MS (m/z): 263.1 (MH⁺) HPLC (method A): rt=8.14 min

¹H-NMR (δ, DMSO-d₆): 0.9-1.1 (dq,2H, CH₂); 1.4 (s,9H, (CH₃)₃); 1.45-1.7(m, 5H, —CH—CH₂CH₂—O—, 2CH ₂); 2.45(m, 1H, CH-D-phe-alaninol); 2.6-2.8(m, 3H, —CH—N—CH—. —CH—D-phe); 3.0 (m, 1H, CH—NH₂); 3.1-3.5 (m, 4H, —CH₂—O—CH ₂—); 3.8-3.9 (m, 2H, —CH—N—CH—); 7.1-7.3 (m,5H,Ar-D-phe-alaninol).

EXAMPLE 60 (R)4-{2-[2-({1-[(6-Methyl-benzo[b]thiophene-2-carbonyl)-amino]-cyclopentanecarbonyl}-amino)-3-phenyl-propoxy]-ethyl}-piperidine-1-carbamicacid tert-butyl ester (60)

To a solution of2-(6-Methyl-benzo[b]thiophene-2-il)-4-cyclopentyl-1,3-oxazolin-5-one(0.197 gr, PM 285, 0.69 mmol) in 10 mL of DMF is added4-[2-(2-Amino-3-phenyl-propoxy)-ethyl]-piperidine-1-carbamic acidtert-butyl (0.25 gr, 0.69 mmol, PM=362) dissolved in 5 mL of DMF. Thereaction is left at room temperature for 12 hours under stirring.

It is then transferred to a separatory funnel with ethyl acetate and theorganic phase is washed with NaHCO₃ 10%, then with brine and dried onanhydrous Na₂SO₄. After evaporation of the solvent at reduced pressurethe raw reaction product is chromalographed on a flash column (eluentchloroform:methanol 98/2).

0.40 g of4{2[2({1[(6-Methylbenzo[b]thiophene-2-carbonyl)-amino]-cyclopentanecarbonyl}-amino)-3-phenyl-propoxy]-ethyl}-piperidine-1-carbamicacid tert-butyl ester 60 are obtained (yield 90%, PM=647, 0.62 mmol).

MS (m/z): 648.2 (MH⁺) HPLC(method A): rt=14.77

¹H-NMR (δ, DMSO-d₆): 0.9 (m,2H,CH₂);1.2-2.0 (m, 21H, 3CH₃, 6CH₂,); 2.15(m,1H, CH—CH₂—CH₂—O); 2.45 (s,3H,CH₃); 2.6-2.8 (m, 4H, CH₂-D-phenylalaninol, CH—N—CH—); 3.2-3.4 (m, 4H, —CH ₂—O—CH ₂—); 3.85 (m,2H, —CH—N—CH—); 4.05 (m, 1H, —CH—CH₂-Phe); 7.1-7.2 (m,5H,Ar-D-phenylalaninol), 7.25 (dd,1H, NH—CH D-phenylalaninol), 7.3(d,1H,C(5)-H), 7.8 (s,1H,C(6)-H), 7.85 (d,1H,C(4)-H), 8.2 (s, 1H,C(3)-H), 8.45 (s, 1H,

EXAMPLE 61 (R) 6-Methyl-benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-2-(2-piperidin-4-yl-ethoxy)-ethylcarbamoyl]-cyclopentyl}-amide*Hydrochloride (61)

0.4 gr. of4{2[2({1[(6Methylbenzo[b]thiophene-2-carbonyl)-amino]-cyclopentanecarbonyl}-amino)-3-phenyl-propoxy]-ethyl}-piperidine-1-carbamicacid tert-butyl ester (60, PM=647, 0.62 mmol) are dissolved in 5 mL ordioxane and 20 mL or a solution of HCl 4N in dioxane are added, understirring and at room temperature; after 30 minutes the solution isevaporated and the gummy residue is dried twice by ethyl ether. Thesolid formed is triturated with ethyl ether and filtered on paperobtaining 0.33 g of 6-Methyl-benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-2-(2-piperidin-4-yl-ethoxy)-ethylcarbamoyl]-cyclopentyl}-amide*Hydrochloride 61 (PM=583.5, 91% yield, 0.56 mmol)

MS (m/z): 548.1 (MH⁺) HPLC(method A): rt=8.49 min

EXAMPLE 62 (R) 6-Methyl-benzo[b]thiophene-2-carboxylic acid[1-(1-benzyl-2-{2-[1-tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-ethoxy}-ethylcarbamoyl)-cyclopentyl]-amide(62)

100 mg of 6-Methyl-benzo[b]thiophene-2-carboxylic acid{1-[1-benzyl-2-(2-piperidin-4-ylethoxy)ethylcarbamoyl]-cyclopentyl}-amide*Hydrochloride (61, PM=583.5, 0.17 mmol) and 58 mg of4-tetrahydropyranyl aldehyde (PM=114, 0.51 mmol) are dissolved in 20 mLof anhydrous DCM. 110 mg of sodium triacetoxyborohydride (PM=212, 0.51mmol) are added to this opalescent solution. The mixture is left understirring and under nitrogen at room temperature for 2 hours. The solventis evaporated at reduced pressure and extracted with ethyl acetatetransferring the mixture to a separatory funnel; the organic phase iswashed with NaHCO₃ brine and is placed to dry on Na₂SO₄. Afterevaporating the solvent at reduced pressure, the raw reaction product ispurified on a flash column (eluent Chloroform:MeOH 95/5), obtaining 70mg of 6-Methyl-benzo[b]thiophene-2-carboxylic acid[1-(1-benzyl-2-{2-[1-(tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-ethoxy}-ethylcarbamoyl)-cyclopentyl]-amide62 (PM=645, 0.108 mmol, 64% di yield)

MS (m/z): 646.1 (MH⁺) HPLC(method A): rt=9.01 min

¹H-NMR (δ, DMSO-d₆): 1.0-1.7 (m,18H,CH₂);1.85-2.0 (m,5H, CH—N—CH,CH—O—CH—tetrahydropyran, CH—CH₂—CH₂—N); 2.15 (m,1H, CH—CH₂—N); 2.45(s,3H,CH₃); 2.65-2.8 (m, 4H, CH ₂-D-phenyl-alaninol, CH—N—CH); 3.2-3.4(m, 6H, —CH ₂—O—CH ₂—, —CH—O—CH-tetrahydropyran); 3.85 (m, 2H, —CH—O—CH—tetrahydropyran); 4.05 (m, 1H, —CH—CH₂— Phe); 7.1-7.2 (m,5H,Ar-D-phe-alaninol), 7.25 (dd,1H, NH—CH D-phe-alaninol), 7.3(d,1H,C(5)-H), 7.8 (s,1H,C(6)-H), 7.85 (d,1H,C(4)-H), 8.2 (s, 1H,C(3)-H), 8.45 (s, 1H, CONH).

HPLC Methods:

Mobile phase: A=H₂O+0.1% TFA; B=MeCN+0.1% TFA

Method A

Column: Symmetry C18, 3.5 micron (4.6×100 mm)

Gradient: 1′ isocratic 10% B, 10′ of 10% B at 80% B

Flow velocity: 1 mL/min

λ=220, 254 nm.

Assessment of the antagonist activity on NK-2 receptors was performedwith binding and functional tests according to prior descriptions in theliterature for NK-2 antagonists.

In particular, affinity of the compounds for the human NK-2 receptor wasassessed in a binding test using membranes of Chinese hamster ovary(CHO) cells, transfected with the NK-2 receptor of human ileum and theradioligand ['251]NKA (Amersham, aspecific activity 2000 Ci/mmol) at aconcentration of 100 pM in competition studies. The substances underexamination were tested in a concentration range from 0.01 nM to 10 mM.At the end of incubation (30 min., 20° C.) the samples were filtered andthe radioactivity was determined using a gamma-counter.

The data in table 1 were obtained for some compounds of general formula(I) and concern the values of affinity to the human NK-2 receptor: TABLE1 Compounds pKi Compounds pKi Example 46 9.2 Example 50 9.9 Example 5110.1 Example 52 10.1 Example 53 8.7 Example 54 10.3 Example 55 10.0Example 62 9.3 Example 58 9.9

The compounds of formula (I) can be handled according to the commonpharmacopoeial techniques in order to prepare formulations suitable fororal, intranasal, parenteral, sublingual, inhalatory, transdermal, localor rectal use according to data known in the literature for this type ofproduct; these forms of administration comprise oral formulations, suchas tablets, capsules, powders, granulated formulations, and oralsolutions or suspensions, formulations for sublingual administration,for intranasal administration for use in aerosol and implantation,formulations for subcutaneous, intramuscular, intravenous, intraocularand rectal administration. The effective doses are 0.1 to 50 mg/kg ofbody weight. For humans the dose may preferably range from 0.5 to 4000mg/day, in particular from 2.5 to 1000 mg according to the patient's ageand to the type of treatment. The treatment is carried out byadministering the required amount to the patient 1 to 4 times per dayfor periods of up to 2 weeks or in any case until remission of symptoms;for chronic diseases, administration can be prolonged for significantlylonger periods of time according to the judgment of the physician.

Thanks to their high antagonist activity on the NK-2 receptor oftachykinins, the present compounds are useful in the treatment ofdiseases in which Neurokinin A plays a pathogenetic role, and namely inthe following diseases:

-   -   chronic obstructive respiratory diseases, such as asthma and        allergic rhinitis, coughs and bronchitis;    -   opthalmic diseases, such as conjunctivitis or vitreoretinopathy;    -   skin problems, such as allergic and contact dermatitis, atopic        dermatitis, eczema, itch, psoriasis, burns, in particular        sunburn;    -   intestinal disorders, such as irritable colon, ulcerous colitis,        Crohn's disease, diarrhoea;    -   gastric diseases, such as nausea or emesis;    -   prostatitis, neurological bladder, urinary incontinence,        cystitis, urethritis, nephritis, erectile dysfunctions;    -   tumor diseases, autoimmune diseases or diseases associated with        AIDS;    -   diseases of the central nervous system, such as anxiety,        depression, schizophrenia, dementia, epilepsy, Parkinson's        disease, Alzheimer's disease, drug and alcohol addiction,        alcoholism, Huntington's chorea, neurodegenerative diseases and        somatic disorders, such as stress;    -   treatment of pain, in particular visceralgia, neuritis,        neuralgia;    -   cardiovascular diseases, such as hypertension, edema,        thrombosis, angina, vascular spasms;    -   inflammatory diseases, such as arthritis, rheumatoid arthritis.

1) Compounds of general formula (I):

wherein: X1 is a —NR6-CO—, —CO—, —NR6-CS— group; R1 is an aryl group selected from pyridine, thiophene, benzene, naphthalene, diphenyl, phenylthiophene, benzothiophene, benzofuran, N-indole substituted by an R7 group, where said aryl group may also be substituted by one or more independent groups selected from halogen, C1-C6 alkyl optionally substituted by not more than three fluorine atoms (i.e. trifluoromethyl group), C1-C6 alkyloxyl, optionally substituted by not more than three fluorine atoms (i.e. trifluoromethyloxyl group), —OH, —NHR7, —N(R7)2, —SR7, —CONHR7, —COR7, —COOR7, —R8COOR7, —OR8COOR7, —R8COR7, —CONHR7, —R8CONHR7, —NHCOR7, -nitro, where R7 is hydrogen or C1-C6 alkyl with a linear or branched chain, and R8 is a C1-C6 alkylene group with a linear or branched chain; R6 is selected from a group consisting of hydrogen or a C1-C6 alkyl with a linear or branched chain; the broken line indicates a possible double bond and n and m may independently be 0, 1, 2; R9 and R10 are selected independently in the hydrogen, C1-C6 alkyl group or may be connected to form an aromatic group selected in a phenyl group; X2 is selected in the group formed of —(CH2)p-, —(CH2)q-CO—, —(CH2)s-O—(CH2)q-, —CH═CH—, —CH═CH—CO—, CH═CH—O—(CH2)q- where p may be 2, 3, 4; q may be 2, 3, 4: and s may be 1, 2; R2 is selected from a group consisting of an aryl-alkyl or aryl radical where the aryl part is selected in a group consisting of benzothiophene, indole, pyridine, pyrrol, benzofuran, thiophene, benzene, naphthalene, imadazole, diphenyl, and may optionally be substituted by one or more substituents selected independently from halogen, C1-C6 alkyl optionally substituted by not more than three fluorine atoms (i.e. trifluoromethyl group), C1-C6 alkyloxyl, optionally substituted by not more than three fluorine atoms (i.e. trifluoromethyloxyl group), —OH, —NHR7, —N(R7)2, —SR7, —CONHR7, —COR7, —COOR7, —R8COOR7, —OR8COOR7, —R8COR7, —CONHR7, —R8CONHR7, —NHCOR7, —nitro, where R7 is hydrogen or C1-C6 alkyl with a linear or branched chain, and R8 is a C1-C6 alkylene group with a linear or branched chain; R3 contains at least a basic amino group and is selected from a group with general formula: —R₄—X₃—R₅ where R4 is selected from a group consisting of: an —NR6- amino group; an aliphatic heterocycle containing one or two heteroatoms selected from N, S and O, and optionally substituted by one or two C1-C6 alkyl groups; X3 can be a simple bond or is selected in the group consisting of (CH2)t-, —CO—, —O—(CH2)t-, —O—, —NH—CO—CH2-, —NH—CO— where t can be 1, 2, 3; R5 is: an aliphatic heterocycle, selected in the group consisting of pyrrolidine, piperidine, morpholine, tetrahydropyran, 1,4-dioxa-8-azaspiro[4,5]decane, dioxane, optionally substituted by one or more C1-C6 alkyl, hydroxymethyl, —OH, cyanomethyl and C1-C6 alkyloxy groups; a group selected from —NR₁₁R₁₂, —OR11 where R_(11,) R₁₂ are independently selected in the group: hydrogen, C1-C6 alkyl; an aryl selected from thiophene, pyridine, furane or phenyl optionally substituted by one or more halogen, C1-C6 alkyl, C1-C6 alkyloxy and OH groups; the pharmaceutically acceptable salts of compounds of formula (I) with organic and inorganic acids selected in the group: hydrochloric, sulphuric, phosphoric, acetic, trifluoroacetic, oxalic, malonic, maleic, fumaric, succinic, tartaric and citric acids; the possible optical isomers in the form of enantiomers or diastereoisomers, pure or in the form of racemic or non-racemic mixtures of said isomers; the “retro-inverted” compounds, that is, compounds having the structure of general formula (I), but wherein one or two amide bonds are reversed. 2) Compounds as claimed in claim 1, wherein the amino acid residue of general formula II:

is selected in the group consisting of amino acid residues of: 1-aminocyclohexane-I-carboxylic acid, 1-aminocyclopentane-I-carboxylic acid, 1-aminocyclopent-3-ene-1-carboxylic acid, 1-aminoindane-I-carboxylic acid, 2-aminoindane-2-carboxylic acid, 2-aminotetraline-2-carboxylic acid, and the other groups are as defined above. 3) Compounds as claimed in claim 2, wherein: X1 is a CO group R1 is an aryl group selected from naphthalene, benzothiophene, benzofuran, N-indole substituted by an R7 group; where said aryl group is optionally substituted by one or more groups independently selected from halogen, C1-C6 alkyl optionally substituted by not more than three fluorine atoms (i.e. trifluoromethyl group), C1-C6 alkyloxy optionally substituted by not more than three fluorine atoms (i.e. trifluoromethoxyl group), —OH, —NHR7, —N(R7)2, —SR7, —CONHR7, —COR7, —COOR7, —R8COOR7, —OR8COOR7, —R8COR7, —CONHR7, —R8CONHR7, —NHCOR7, -nitro, where R7 is hydrogen or a linear or branched C1-C6 alkyl chain, and R8 is a linear or branched C1-C6 alkylene group; R6 is selected from a group consisting of hydrogen or a C1-C6 alkyl with a linear or branched chain; the amino acid residue of general formula II:

is selected in the group consisting of amino acid residues of: 1-aminocyclohexane-I-carboxylic acid, 1-aminocyclopentane-I-carboxylic acid, R2 is a phenylmethyl group optionally substituted on the phenyl part by one or two groups independently selected from halogen, C1-C6 alkyl, CI-6 alkyloxy, and OH X2 is as defined hereinbefore R3 contains at least one basic amino group and represents a group: —R₄—X₃—R₅ wherein R4 is selected in the group: an —NR6- amino group, an aliphatic heterocycle selected from piperidine, piperazine, pyrrolidine optionally substituted by one or two C1-C6 alkyl groups; X3 may be a simple bond or is selected in the group consisting of —(CH2)t-, —CO—, where t may be 1, 2, 3; R5 is: an aliphatic heterocycle selected in the group consisting of tetrahydropyran, morpholine, piperidine, optionally substituted by one or more groups C1-C6 alkyl, hydroxymethyl, —OH, cyanomethyl, and C1-C6 alkyloxy; a group selected from —NR₁₁R₁₂, —OR11 where R_(11,) R₁₂ are independently selected in the group: hydrogen, C1-C6 alkyl; an aryl selected from thiophene, furane or phenyl optionally substituted by one or more halogen, C1-C6 alkyl, C1-C6 alkyloxy or OH groups. 4) Compounds as claimed in claim 3, wherein: XI is a —CO-group; RI is a benzothiophene group, which may optionally be substituted by one or two groups selected independently from halogen, CI-C6 alkyl optionally substituted by not more than three fluorine atoms, the amino acid residue of general formula (III) is 1-aminocyclopentane-I-carboxylic acid, R6 is hydrogen; R2 is phenyl-methyl, with the phenyl group optionally substituted by a C1-C6 alkyl; X2 is selected in the group consisting of —(CH2)p-, —(CH2)q-CO—, —(CH2)s-O—(CH2)q-, —CH═CH—, —CH═CH—CO—, where p is 3; q is 2: and s is 1; R3 contains at least one basic amino group and represents a group: —R₄—X₃—R₅ wherein R4 is selected from a group consisting of: an —NR6- amino group; an aliphatic heterocycle selected from piperidine and piperazine X3 may be a simple bond or is selected from the group consisting of —(CH2)t-, —CO—, where t may be 1, 2, 3; R5 is: a tetrahydropyran, a group selected from —NR₁₁R₁₂, —OR11 where R_(11,) R₁₂ are independently selected in the group: hydrogen, methyl; a phenyl. R6 is hydrogen. 5) Compounds as claimed in claim 4, which are as follows: (R) Benzo[b]thiophene-2-carboxylic acid {1-[1-benzyl-3-(3-dimethyl amino-propylcarbamoyl)-allylcarbamoyl]-cyclopentyl}-amide (R) Benzo[b]thiophene-2-carboxylic acid {1-[1-benzyl-3-(2-dimethyl amino-ethylcarbamoyl)-allylcarbamoyl]-cyclopentyl}-amide (S) Benzo[b]thiophene-2-carboxylic acid {1-[1-benzyl-3-(3-dimethyl amino-propylcarbamoyl)-propylcarbamoyl]-cyclopentyl}-amide (S) Benzo[b]thiophene-2-carboxylic acid {1-[1-benzyl-3-(2-dimethyl amino-ethylcarbamoyl)-propylcarbamoyl]-cyclopentyl}-amide (S) Benzo[b]thiophene-2-carboxylic acid {1-[1-benzyl-4-(4-benzyl-piperidin-1-yl)-butylcarbamoyl]-cyclopentyl}-amide (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid (1-{1-benzyl-4-oxo-4-[4-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid (1-{1-benzyl-4-oxo-4-[4-(tetrahydro-pyran-4-yl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid (1-{1-benzyl-4-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-4-oxo-butylcarbamoyl}-cyclopentyl)-amide (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid (1-{1-benzyl-4-[4-(tetrahydro-pyran-4-ylmethyl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid (1-{1-benzyl-4-[4-(tetrahydro-pyran-4-carbonyl)-piperazin-1-yl]-butylcarbamoyl}-cyclopentyl)-amide (S) 6-Methyl-benzo[b]thiophene-2-carboxylic acid (1-{1-benzyl-4-[1-(tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-butylcarbamoyl}-cyclopentyl)-amide (R) 6-Methyl-benzo[b]thiophene-2-carboxylic acid [1-(1-benzyl-2-{2-[1-(tetrahydro-pyran-4-ylmethyl)-piperidin-4-yl]-ethoxy}-ethylcarbamoyl)-cyclopentyl]-amide. 6) Compounds as claimed in claim 1 for the preparation of pharmaceutical compositions useful in the treatment of diseases linked to stimulation of the NK-2 receptor. 7) Compounds as claimed in claim 6 for the preparation of pharmaceutical compositions for the treatment of respiratory diseases such as asthma, allergic rhinitis, ophthalmic diseases such as conjunctivitis, skin diseases such as allergic and contact dermatitis and psoriasis, intestinal disorders such as irritable colon syndrome, ulcerous colitis and Crohn's disease, urinary diseases such as cystitis and incontinence, erectile dysfunctions, diseases of the central nervous system such as anxiety, depression or schizophrenia, or tumor diseases, autoimmune diseases or diseases related to AIDS. 8) Pharmaceutical compositions containing as active ingredient at least one of the compounds of general formula (I) as claimed in claim 1, or mixtures thereof. 9) Pharmaceutical compositions as claimed in claim 8, also containing pharmaceutically acceptable excipients and diluents. 10) Pharmaceutical compositions as claimed in claim 8, for the treatment of diseases linked to stimulation of the NK-2 receptor and in particular for the treatment of respiratory diseases such as asthma and allergic rhinitis, opthalmic diseases such as conjunctivitis, skin diseases such as allergic and contact dermatitis and psoriasis, intestinal disorders such as irritable colon, ulcerous colitis and Crohn's disease, urinary diseases such as cystitis and incontinence, erectile dysfunctions, diseases of the central nervous system such as anxiety, depression and schizophrenia, or tumor diseases, autoimmune diseases or diseases related to AIDS.
 11. Pharmaceutical compositions as claimed in claim 9, for the treatment of diseases linked to stimulation of the NK-2 receptor and in particular for the treatment of respiratory diseases such as asthma and allergic rinithis, ophtalmic diseases such as conjunctivitis, skin diseases such as allergic and contact dermatitis and psoriasis, intestinal disorders such as irritable colon, ulcerous colitis and Crohn's disease, urinary diseases such as cystitis and incontinence, erectile dysfunctions, diseases of the central nervous system such as anxiety, depression and schizophrenia, or tumor diseases, autoimmune diseases or diseases related to AIDS. 